Listening to Leroy Hood

When Dr. Leroy Hood talks there’s a reason a lot of people in the fields of medicine, biology and genetics listen.

Beyond his pioneering work in developing automated gene sequencing, Hood helped found companies as diverse as Amgen and Applied Biosystems; he is one of only about a dozen people who belong to the National Academy of Sciences, the National Academy of Engineering and the Institute of Medicine; and now as president of the Seattle-based Institute for Systems Biology, Hood is focusing his broad experience into researching immunology, neurobiology, cancer biology, molecular evolution and systems medicine.

He is also an advocate of personalized medicine and what he calls “P-4 Medicine” or an approached to medicine that is predictive, preventative, personalized and participatory. He is an advisor to next year’s Personalized Medicine World Conference and recently spoke to the Spittoon about his work and new developments in the field.

You and the Institute for Systems Biology were recently involved in sequencing a family of four. Why did you do this and what did you learn? Does the experience give you any insight into the future value of sequencing either full genomes or exomes?

Dr. Hood: “We sequenced genomes of a family of four where the parents were normal and the two kids each had two genetic diseases. We were convinced that it might be easier to find disease genes with all of these data. We found that the ability to use the principles of Mendelian genetics lead to quite remarkable opportunities. First, we were able to correct 70 percent of the DNA sequencing errors. Second, we could immediately identify rare variants and distinguish them from DNA sequencing errors if two or more members of the family had the rare variant. Third, we were able to determine the haplotypes of all the chromosomal pairs for all members of the family – and could accurately determine the sites of recombination. Fourth, we could determine the human intergenerational mutation rate for the kids – roughly 35 mutations per kid. Finally, we narrowed the disease gene candidates down to four – and the assignments were straightforward. We feel strongly that human genomes should be completely sequenced in the context of families.”

Twenty-five years ago you advocated for the Human Genome Project. Is there something equivalent that should be advocated for now? Why?

Dr. Hood: “We are now pushing the Human Proteome Project. This project has striking similarities to the human genome project. We need to develop good assays for all human proteins. We need to develop many technologies for measuring the enormous complexity of proteins (mutations, RNA splicing variants, chemical modifications, dynamical three-dimensional structures, new strategies for identifying functions, etc.). We also need to develop parallel computational and mathematical tools. We need to develop accurate in silico tools for determining 3-dimensional structures of proteins and peptides. We need to develop the computational tools to democratize proteomics – make this discipline accessible to all scientists. Proteins execute the functions of life – and are key in the end to understanding both simple and complex biological functions.”

Two of the four Ps you talk about with P-4 medicine are “personalized” and “participatory.” What are some of the best examples, in your opinion, of this kind of medicine right now?

Dr. Hood: “I think some of the best examples for personalized medicine have to do with sequencing tumors, identifying mutated signal transduction molecules and then choosing therapies based on the data from the individual tumors. This has been done for melanoma, breast cancer and colon cancer. I think patients are just coming into their own for the participatory group. Examples are the groups of patients that have gotten together to deal with their diseases (cancer, neurodegenerative, etc.) A second example, are those few patients who are beginning to quantify their own personal data to optimize wellness. Larry Smarr has recently written a wonderful paper on his 10 year quest to optimize his own wellness.”

How do you envision medicine will be more personalized and include more participation in the future?

Dr. Hood: “In the future we will gather billions of data points on each patient and use this to sculpt their individual potential for wellness and potential for disease. We will be able more and more to provide individual advice to the patient on how to optimize their health. A second area is that we will be able to more and more effectively divide or stratify disease into its various subtypes. For example, breast cancer has at least five different subtypes by histological and molecular features. This stratification is essential for creating an impedance match with the right drugs – so the mantra of personalized medicine is the right drug at the right time for the right patient–and increasingly we will see this. I think as patients gain more and more digitized data about their own health status – they will more and more actively participate in their own wellness.”

Dr. Hood: “I think it could have an enormous impact – particularly if you join with medical scientists to take advantage of these unique patient populations. This is something I personally am extremely interested in exploring.”

You recently said that within 10 years every company in the health care industry would have to rewrite its business plan because of the changes coming. What companies are successfully changing their approach to handle the transformations you foresee?

Dr. Hood: “I believe that a systems approach to medicine will increasingly lead to a better understanding of disease mechanisms, will make blood a window into studying health and disease, will develop powerful tools for the stratification of disease, will generate new, rapid and ineffective ways to identify optimal drug targets for given disease, will be able to analyze the responses of multiple organs to a given disease and will increasingly begin to focus on optimizing wellness for the individual. So there are opportunities for many companies to begin changing. I think in the beginning new companies will lead the charge in these areas – and once they have demonstrated the power of their approaches – then the larger companies will follow. An example is that drug companies are beginning to realize the importance of companion drugs – that allow the right population of patients to be identified for the drug.

In your career you’ve made a number of important breakthroughs, on high-speed DNA sequencers for instance. Where do you hope to make your next big breakthrough?Dr. Hood: “I see many important areas where there can be fundamental breakthroughs. First, in applying the tools of genomics effectively to the identification of actionable opportunities for individual patients – by actionable I mean learning something about the patient that will allow the physician to advise the patient and change their health status. Second, I think there will increasingly be advances in proteomics that will allow us to understand how proteins go about executing their functions of life – and understanding how proteins behave abnormally in disease. I think a particularly important area is to develop new protein capture agents that will replace antibodies – reagents that are easily generated, that are stable and are inexpensive. I think the area of detailed single-cell analysis will transform our understandings of biology and disease. Finally, I think induced pluripotential stem cells (iPS) will be used for understanding biology and disease mechanisms, for diagnosis and ultimately for therapy – and this will transform how we approach biology. I hope to push the vision of P4 medicine and to succeed in bringing it to patients. I hope in the next few years to persuade a small single payer country to adopt P4 medicine.”

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